mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake
Open accessAbstract
How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.
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mTOR regulates the self-renewal and differentiation of HSCs and intestinal stem cells.
“mTOR, a potent activator of protein translation and inhibitor of autophagy, has been shown to regulate the self-renewal and differentiation of HSCs and intestinal stem cells79,80.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [79]
Calorie restriction can boost or preserve aged stem cell activity by raising brain-derived neurotrophic factor in the brain.
“CR can also enhance or maintain stem cell function during aging by increasing the expression of brain-derived neurotrophic factor in the brain and reducing the mTOR complex 1 (mTORC1) pathway in intestine79,112.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [79]
Calorie restriction can boost or preserve aged stem cell activity by lowering mTORC1 signaling in the intestine.
“CR can also enhance or maintain stem cell function during aging by increasing the expression of brain-derived neurotrophic factor in the brain and reducing the mTOR complex 1 (mTORC1) pathway in intestine79,112.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [79]
Paneth cells supply key niche factors such as epidermal growth factor, Wnt3A and Notch ligand.
“Paneth cells, found in close association with intestinal stem cells in humans and mice, are an important source of niche factors, including epidermal growth factor, Wnt3A and Notch ligand79,156, although the effect of aging on their activity is yet to be elucidated.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [79]
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Self-citation
- Authors
- Yilmaz, Ö. H., Katajisto, P., Lamming, D. W., Gültekin, Y., Bauer-Rowe, K. E., Sengupta, S., Birsoy, K., Dursun, A., Yilmaz, V. O., Selig, M., Nielsen, G. P., Mino-Kenudson, M., Zukerberg, L. R., Bhan, A. K., Deshpande, V., & Sabatini, D. M.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Nature
- Published
- 2012-05-20
- Volume
- 486
- Issue
- 7404
- Pages
- 490-495
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3387287
- OpenAlex
- W2113486346
- Cited by
- 753
- References
- 33
- Citations by year
- 2026: 38 · 2025: 45 · 2024: 44 · 2023: 58 · 2022: 53 · 2021: 75 · 2020: 69 · 2019: 54 · 2018: 63 · 2017: 56 · 2016: 39 · 2015: 39 · 2014: 52 · 2013: 47 · 2012: 19
- FWCI
- 20.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (F32AG032833)
- National Cancer Institute (T32CA09216, CA129105, CA103866, R01CA103866, R01CA129105, T32CA009216)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1, Paneth cells, intestinal stem cells, intestinal stem cell niche, caloric restriction, BST1, cyclic ADP-ribose, paracrine signaling, stem cell self-renewal, intestinal regeneration, nutritional status, rapamycin, lifespan
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Energy Intake, Cell Count, Cell Division, Female, Intestines, Longevity, Male, Proteins, Regeneration, Stem Cells, Signal Transduction, Antigens, CD, Paneth Cells, Paracrine Communication, Sirolimus, Caloric Restriction, ADP-ribosyl Cyclase, Cyclic ADP-Ribose, Multiprotein Complexes, Mice, Stem Cell Niche, TOR Serine-Threonine Kinases, GPI-Linked Proteins
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